Know All About: Retinopathy of Prematurity

Classification

A committee for ROP classification was formed in 1984, which proposed an international classification of ROP (ICROP) by dividing the retina into three zones, extending from posterior to anterior retina and describing the extent of ROP in clock-hours of involvement. However, with the advances in retinal imaging techniques, a revised ICROP classification was put forth which described the zones better.

Zones

Three concentric zones, centred on the retina define the antero-posterior location of retinopathy.

Zone I: With optic disc as the centre, and twice the distance from the disc to fovea, the circle formed is zone I. Using a 25 or 28 diopter (D)-condensing lens, when the nasal edge of the optic disc is kept at one edge, the temporal field of view is zone I extent.

Zone II: It starts from the edge of zone I and extends till the ora serrata nasally, with a corresponding area temporally.

Zone III: Zone III is the remaining crescent of retina temporally.

Extent of retinopathy

The extent of the ROP is documented by the number of clock hours involved. For the observer examining each eye, the temporal side of the right eye is 9 o’clock and that of the left eye is 3 o’clock and vice versa.

Stages of ROP

It denotes the degree of vascular changes. There are five stages.

Stage 1 – demarcation line: A demarcation line is seen between the vascular and avascular retina. It is a thin structure that lies in the plane of the retina.

Stage 2 – ridge: The demarcation line grows to occupy a volume and has a height and width to form a ridge above the plane of the retina. Small tufts of new vessels also called as “popcorn” vessels may be seen posterior to the ridge.

Stage 3 – ridge with extraretinal fibrovascular proliferation: In this stage extraretinal fibrovascular tissue is seen arising from the ridge into the vitreous. It may be continuous or non-continuous and is posterior to the ridge.

Stage 4 – subtotal retinal detachment: Here a partial detachment of the retina is seen which may be exudative or tractional. It is subdivided into the following : (1) Partial retinal detachment not involving the fovea (stage 4A) (Figure 1D; and (2) Partial retinal detachment involving the fovea (stage 4B).

Stage 5 – total retinal detachment: Here a total retinal detachment is seen as a child usually presents with leukocoria (white pupillary reflex).

Plus disease: It is an indicator of the severity of the disease and is defined as venous dilation and arterial tortuosity of the posterior pole vessels.

Pre-plus disease: It is defined as posterior pole vascular dilation and tortuosity which is more than normal but less than a plus disease.

Aggressive posterior ROP: This refers to an uncommon, rapidly progressive, form of ROP previously referred to as “rush disease”. It is characterized by a posterior location, severe plus disease, and flat intraretinal neovascularization. It can progress very fast to stage 5 ROP and blindness, if not intervened early. The flat neovascularization can be quite subtle and can easily confuse less experienced examiners.

Treatment for ROP – a present concept

Although the ICROP classification gave a detailed classification of ROP, it never recommended when to treat ROP. Following are the treatment stages of ROP.

Threshold ROP: The cryotherapy for retinopathy of prematurity (CRYO-ROP) study stated that treatment should be imparted to eyes with threshold disease, defined as stage 3 ROP in zone I or II, having five contiguous or eight discontiguous clock hours with plus disease  This was the previous “cut off” for treatment.

Pre-threshold ROP: The early treatment for retinopathy of prematurity (ETROP) study redefined these guidelines. They defined the actively treatable and observational types of pre-threshold ROP as “type 1” (high-risk prethreshold ROP) and “type 2” ROP respectively. “Type 1 ROP” is defined as (1) Any stage of ROP in the zone I with plus disease; or (2) Stage 3 in the zone I without plus; or (3) Stages 2 or 3 in zone II with plus disease. These are the modified guidelines for treatment. “Type 2 ROP” is defined as stages 1 or 2 in the zone I (Figure 3C) without plus or stage 3 in zone II without plus. These can be observed and watched at one week or less follow-up. Cases having stages 1 or 2 in zone II require two week follow up, while stages 1 or 2 in zone III require three weekly follow-ups.

Treatment modalities

Cryotherapy: This involves treatment of the avascular retina using of a cryoprobe in order to reduce unfavourable outcomes of ROP like retinal folds and retinal detachment. Cryotherapy, however, is stressful for the babies, requires general anaesthesia and creates lot of periocular inflammation. It is therefore no more the treatment of choice.

Indirect laser photocoagulation: Laser photocoagulation of the peripheral retina using indirect delivery system has proved to be the gold standard, time tested and successful means of treatment since many years. Laser photocoagulation using infrared diode laser forms a portable mode of treatment and can be performed in the nursery by skilled professionals (Figure 3D). The biggest advantage is that it can be done under topical anesthesia. However many institutions prefer general anesthesia for patient comfort. Laser ablation covers the relatively hypoxic retina into anoxic, thereby reducing stimulus for new vessel formation and disease progression. The ETROP study from its six years analysis confirmed that eyes with type 1 ROP benefited from laser treatment at high risk pre threshold stage. This failure rate of 9.6%, was better than the results shown by the CRYO-ROP study.

Cryotherapy or laser photocoagulation, ablation has its own demerits and causes destruction of the retina amounting to significant visual field loss. Pharmacologic therapy is thus ushering a new era of ROP management.

Anti-vascular endothelial growth factors drugs: Anti-vascular endothelial growth factor (VEGF) drugs directly block the effects of VEGF, and a single intravitreal injection is less time consuming and less expensive as compared to lasers. Exceptionally successful results with anti-VEGF drugs in adult retinal vascular diseases led to its trial in paediatric retinopathy as a monotherapy as well as in combination with lasers. Intravitreal bevacizumab as an initial mono therapy was reported to cause regression of type 1 ROP in 88% cases with 9% requiring additional laser treatment and 1% requiring additional injection. The BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of ROP) study is the only randomised trial done comparing anti-VEGF vs conventional laser. It suggested superiority of anti-VEGF treatment over conventional laser therapy for stage 3+ ROP in zone I. Superiority in severe ROP in zone II could not be established due to inadequate sample size. Safety is a major concern with use of anti-VEGF drugs in paediatric age group and this study could not prove it because of a short follow up. Recent studies also shown that that systemic VEGF levels remain suppressed for 8 wk after intravitreous bevacizumab injection.

Regarding the best approach, laser treatment is still the gold standard and anti-VEGF therapy should be tried only in selected cases.

Surgical management is reserved for advanced stages of ROP (stages 4 and 5). The stage of ROP and features specific to each eyes guide the choice of surgical technique. It is shown that best anatomical and visual outcome can be attained if surgical intervention is done at 4A ROP as it halts progression to worse stages. The surgical options available for stage 4 ROP are lens sparing vitrectomy or scleral buckling. For stage 5, vitrectomy with lensectomy or open sky vitrectomy can be performed. Visual outcome for stages 4B and 5 is very poor and can lead to permanent visual impairment.

Periodic follow up and the burden of visual morbidity then become the prime concerns after the retinopathy is adequately treated. Visual rehabilitation can be achieved only through an integrated coordination between the pediatricians, ophthalmologists, paramedicals and parents. With the advances in screening tools, it may be hoped that the occurrence of severe retinopathy or severe visual morbidity from ROP may be reduced in future.